An International Asset Map of Clinicians, Educators, and Researchers Pursuing Better Medicine Use in Children: Initial Findings.

The world's 1.89 billion children (age 0-14) too frequently receive treatments that have not been validated through clinical pharmacology research, especially in low- and middle-income countries. Initial findings from an international asset map of professionals and clinician scientists available to address the needs for education, research, and treatment support suggest a critical shortage of clinical pharmacologists, clinical pharmacists, and other professionals with advanced training in the evaluation of therapies for childhood conditions and illnesses. A total of 497 individuals responded to a survey conducted between May 2015 and February 2016. An alarming signal is apparent showing that, while the overall resource pool is unquestionably limited, 87% of relevant qualified personnel are located in high-income countries. The data suggest an urgent need for targeted training in pediatric clinical pharmacology, with particular focus on the needs in Africa, Latin America, and most of Asia.

Pediatric clinical drug trials in low-income countries: key ethical issues.

Potential child participants in clinical research trials in low-income countries are often vulnerable because of poverty, high morbidity and mortality, inadequate education, and varied local cultural norms. However, vulnerability by itself must not be accepted as an obstacle blocking children from the health benefits that may accrue as an outcome of sound clinical research. As greater emphasis is placed on evidence-based treatment of children, it should be anticipated that there will be a growing call for agreement on principles to guide clinical investigations in low-income countries. There is now general acceptance of the view that children must be protected from non-evidence-based interventions and from substandard treatments. The questions remaining relate to how best to stimulate clinical research activity that will serve the needs of infants, children, and youth in developing countries and how best to assign priority to ethically sound research that will meet their clinical requirements. In low-income countries, 39 % of citizens are 13 years of age or younger, and consequently it is certain that clinical investigations of some new therapeutic products will be conducted there more frequently. This review offers some suggestions for approaches that will help to achieve more effective ethical consideration, including (1) improving the quality of research ethics boards; (2) fostering collaborative partnerships among important stakeholders; (3) making concerted efforts to build capacity; (4) improving the quality of the consent and waiver process; and (5) developing improved governance for harmonized ethics platforms. Continuing support by international organizations is required to sustain the establishment and maintenance of stronger research ethics boards to protect children enrolled in clinical trials. This review underscores the importance of developing a culture of solidarity and true partnership between developed and low-income country organizations, which will allow all those involved, and especially child patients, to benefit from the advancement of therapeutics.

Eradication of severe neonatal systemic candidiasis with amphotericin B lipid complex.

OBJECTIVE: To report the successful use of amphotericin B lipid complex in treating severe systemic candidiasis in a very-low-birth-weight infant. CASE SUMMARY: A preterm female infant, born at 25 weeks' gestational age with a birth weight of 870 g, had received full supportive care in the neonatal intensive care unit (NICU), including mechanical ventilation, total parenteral nutrition, and placement of central venous catheters. At seven weeks of age, she developed severe disseminated candidiasis, which failed to respond to conventional amphotericin B and fluconazole therapy. Her progressive deterioration was reversed only after amphotericin B lipid complex (A-complex) was substituted for conventional amphotericin B. The improvement in her condition was impressive, and she made a full recovery without any adverse effect. DISCUSSION: With increased reliance on invasive technologies for life support, systemic candida infections have become increasingly common among premature infants in the NICU. Such infections are potentially fatal for the high-risk neonate. A literature review shows limited documentation of the use of lipid-based formulations of amphotericin B, especially A-complex, in preterm infants. However, the collective experience with these products appears to show that they are effective and cause fewer adverse effects than conventional amphotericin B. The infant reported here had shown progressive deterioration from disseminated candidiasis until conventional amphotericin B therapy was replaced with A-complex. Her recovery corresponded to the clearance of the candidemia. CONCLUSIONS: With favorable results and increasing experience with lipid-based formulations of amphotericin B, it is reasonable to consider these new formulations as therapy for candidemia in preterm infants who are at a high risk of nephrotoxicity or who have failed conventional therapy.

Flumazenil's reversal of myoclonic-like movements associated with midazolam in term newborns.

Sedation is an important aspect of care for critically ill newborns. Proper sedation reduces stress during procedures such as mechanical ventilation. Midazolam, a short-acting benzodiazepine, is widely administered as a sedative in newborn intensive care units but is not without side effects. Three term newborns developed myoclonic-like abnormal movements after receiving midazolam. In one, flumazenil controlled the abnormal movements. Flumazenil is a potent benzodiazepine antagonist that competitively blocks the central effects of benzodiazepines. It can reverse the sedative effects of benzodiazepines occurring after diagnostic or therapeutic procedures or after benzodiazepine overdose. Flumazenil may be considered in cases of abnormal movements associated with midazolam. However, further studies are needed to provide guidelines for the administration of this drug in newborns.

Effect of domperidone on milk production in mothers of premature newborns: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Varying degrees of success have been reported with strategies to increase milk production when lactation is failing. The objective of this study was to investigate the efficacy of domperidone in augmenting milk production in mothers of premature newborns. METHODS: Twenty patients were randomly assigned to receive either domperidone or placebo for 7 days. Milk volume was measured daily. Domperidone levels were measured in randomly selected milk and serum samples on day 5 of the study. Serum prolactin levels were measured before the start of the study, on day 5 and on day 10 (3 days after the last dose of the study medication). RESULTS: Data from 16 patients were available for analysis (7 in the domperidone group and 9 in the placebo group). When compared with baseline values, the mean increase in the volume of milk production from day 2 to 7 was 49.5 (standard deviation [SD] 29.4) mL in the domperidone group and 8.0 (SD 39.5) mL in the placebo group (p < 0.05); proportionally this represented an increase of 44.5% and 16.6% respectively. The serum prolactin levels were similar in the 2 groups at baseline; by day 5 they were significantly higher in the domperidone group than in the placebo group, returning to baseline levels in both groups 3 days after the last dose of the study medication. Very small amounts of domperidone were detected in the breast milk samples. INTERPRETATION: In the short term domperidone increases milk production in women with low milk supply and is detected at low levels in breast milk.

Does thiopentone delay recovery in children premedicated with midazolam?

This prospective, randomized trial of paediatric surgical outpatients, premedicated with oral midazolam, was designed to determine if an intravenous thiopentone induction of anaesthesia prolongs postoperative recovery compared to an inhalation induction with halothane. One hundred children, one to ten years of age, undergoing ENT surgical procedures of 30-60 min duration received midazolam 0.5 mg.kg-1 with atropine 0.03 mg.kg-1 and were randomized to either halothane (Group 1, n = 50) or a thiopentone induction (Group 2, n = 50) technique, followed by a standardized anaesthetic-protocol. Time to extubation was significantly greater in the thiopentone group (8.8 +/- 4 min vs 7.1 +/- 3 min, P < 0.05). Patients receiving thiopentone were also more sedated than the halothane group on arrival in the PARR (3.9 +/- 1.5, 3.3 +/- 1.7, respectively P < 0.05), but the differences disappeared after 30 min. Children premedicated with oral midazolam who receive an intravenous thiopentone induction have a slightly prolonged emergence from anesthesia compared to children induced with halothane.

Current strategies in the management of bronchopulmonary dysplasia: the role of corticosteroids.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease of multifactorial etiology that develops in some premature neonates who survive hyaline membrane disease (HMD). The role of corticosteroids as a cause of ongoing secondary damage in BPD remains speculative, but strategies to control this reactive inflammation form the basis for the use of corticosteroids. In several controlled clinical trials conducted to assess the role of corticosteroids in BPD, dexamethasone has been administered at a dose of 0.5 mg/kg/day, followed by a tapering regimen. Consistent benefits of corticosteroid use have been a decrease in the number of ventilator days and a facilitation of extubation. Common, often transient, side effects include hypertension, hyperglycemia, and poor weight gain. More serious side effects include myocardial hypertrophy, suppression of the hypothalamic-pituitary-adrenal (HPA) axis, perforated gastric ulcers, and gastrointestinal hemorrhage. The long-term effects on growth and development are unknown. The role of corticosteroids in the management of BPD still remains controversial. The dosage, timing, duration of therapy, and length of tapering period for dexamethasone treatment remain unresolved issues. The current literature supports the judicious use of corticosteroids to decrease the number of days on the ventilator and to facilitate extubation in selected infants with BPD. Further controlled clinical trials are necessary before the routine use of corticosteroids in the management of BPD can be recommended.

Myoclonus associated with lorazepam therapy in very-low-birth-weight infants.

Lorazepam is being used with increasing frequency as a sedative in the newborn and the young infant. Concern has been raised with regard to the safety of lorazepam in this age group, especially in very-low-birth-weight (VLBW; < 1,500 g) infants. Three young infants, all of birth weight < 1,500 g, experienced myoclonus following the intravenous administration of lorazepam. The potential neurotoxic effects of the drug (and its vehicle) in this population are discussed. Injectable lorazepam should be used with caution in VLBW infants.

Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant.

The pharmacokinetics of amikacin administered intravenously at currently recommended doses (7.5 mg/kg every 12 h for infants with less than 7 days of life; 7.5 mg/kg every 8 h for infants with greater than 7 days of life) were studied in 28 preterm infants weighing less than 2,500 g (mean +/- standard deviation, 1.38 +/- 0.47 kg; postconceptional age, 30.50 +/- 2.86 weeks). The medication was infused over 45 min. Trough and peak serum samples as well as two additional samples were taken at steady state. The results showed a statistically significant inverse relationship between half-life (8.42 +/- 2.55 h) and postconceptional age (P = 0.002) and a direct correlation between total body clearance (0.84 +/- 0.28 ml/min per kg) and postconceptional age (P = 0.02). These pharmacokinetic data were used to calculate a new dosage schedule for preterm infants. The derived intravenous dosage of amikacin for infants of less than 30 weeks of postconceptional age was 9 mg/kg every 18 h. For infants of greater than 30 weeks of postconceptional age, the dosage was 9 mg/kg every 12 h. Peak and trough levels of amikacin in serum that fell within the therapeutic range were compared by using the currently recommended dosage schedule and the dosage schedule derived from our pharmacokinetic data. There was a reduction in the number of peak and trough levels that fell outside the accepted therapeutic range which was not statistically significant. Extension of the dosing interval and a further increase in the dosage may result in further improvement. Based on these data, the current recommendations are inadequate for the preterm infant. Our derived dosage schedule improved but did not eliminate high trough and low peak levels of amikacin in all infants. The current recommendations should be adjusted for the preterm infant. Ongoing therapeutic drug monitoring is essential to tailor the amikacin dosage to the individual patient.

Cystic fibrosis: enhanced theophylline metabolism may be linked to the disease.

Theophylline disposition (5.5 mg/kg administered intravenously) was studied in 12 patients with cystic fibrosis (CF) and 16 healthy control volunteers. Dietary controls and logs were used to minimize the influence of food on theophylline metabolism. Control subjects were restudied in random order on two subsequent occasions after 2 weeks of either pancreatic enzymes or placebo. Theophylline and its three main metabolites, 1-methyluric acid, 3-methylxanthine, and 1,3-dimethyluric acid, were analyzed in serum and urine by HPLC. The total body clearance, renal clearance, nonrenal clearance, and volume of distribution of theophylline were significantly greater (p less than 0.05) in patients with CF than in control subjects. The increased nonrenal clearance was the result of increased biotransformation to each of the three main metabolites. Patients with CF exhibited enhanced N-demethylation and 8-hydroxylation of theophylline, pathways that appear to be mediated by two different families of P-450 enzymes. Theophylline clearance after 2 weeks of pancreatic enzyme administration in the control subjects was the same as with placebo. Possible reasons for enhanced theophylline biotransformation in CF are discussed.

Medication related nursing activities in a computerized unit dose system. A work sampling analysis.

In planning for decentralization of Pharmacy Services a 2-month study of registered nurses was conducted using the work sampling technique. A quantitative analysis was made of the time which was spent in different medication related activities. Two floors which were thought to be representative of the hospital, a medical floor and a surgical floor, were selected. A classification of activities and a sampling form were prepared and evaluated in a 1 week pilot study. Instantaneous observations were made throughout the 24 hour day at random intervals and recorded on the sampling form. Over 9,400 observations were made. Registered nurses spent 11.39 z 0.66% (mean z SE) of their time in medication related activities.